Impaired insulin secretion, generally in the context of inefficient insulin usage (insulin resistance) is a key step in the pathogenesis of type 2 diabetes. The two main components of secretion are calcium entry into pancreatic beta cells and triggering of insulin granule exocytosis by that calcium. We have modeled both components and their contributions to diabetes. Exocytosis: Granules proceed through a series of stages from synthesis in the cell interior to final readiness for release of their insulin content. In between, they dock at the plasma membrane, are biochemically modified to increase their release probability (Readily Releasable Pool) and finally become colocalized with calcium channels (Immediately Releasable Pool). Calcium concentration drops off steeply with distance from the channels, so close physical association between the two is important for effective release. In collaboration with a large international team of experimental and theoretical beta-cell researchers, we have explored the hypothesis that impaired association of insulin granules with calcium channels plays a role in the reduced insulin secretion on the road to diabetes. We found that in an insulin-secreting cell line (INS-1 cells) exposed to high concentrations of fatty acids, to mimic the diabetogenic state in vivo, the IRP was reduced in size. This was also found in beta cells from cadavers of persons with type 2 diabetes. The protein munc-13 was found to be important for recruiting channels to docked vesicles. The work is described in Ref. # 1 of this report. Calcium and Insulin Oscillations: We have been developing systematically over many years a model for the regulation of the other main component of insulin secretion, calcium entry. We have focused particularly n the mechanisms of calcium oscillations over a range of periods, from seconds to minutes. The slower class of oscillations (5 - 10 minute period) is the main driver of pulsatile insulin concentration in the circulation, which has been shown to be optimal for the response of insulin-sensitive tissues, especially the liver. The central hypothesis of the model is that the oscillations result from the partnership of semi-independent electrical and metabolic oscillators, with the combined system called the Dual Oscillator Model (DOM). The electrical oscillator (EO) is based on negative feedback of calcium onto ion channels, mainly calcium-activated potassium (K(Ca)) channels and ATP-dependent potassium (K(ATP)) channels, and the metabolic oscillator (MO) is governed by feedback of metabolites on the enzyme phosphofructokinase (PFK) in glycolysis. The MO communicates with the EO via the K(ATP) channels, which transduce the metabolic state of the cell (ATP/ADP ratio) into electrical depolarization. K(ATP) channels are of clinical significance as they are a target of insulin-stimulating drugs, such as the sulfonylureas tolbutamide and glyburide, the first class of oral medications developed for the treatment of Type 2 Diabetes. Severe gain-of-function mutations of K(ATP) are a major cause of neo-natal diabetes mellitus, whereas moderate gain-of-function mutations have been linked in genome-wide association studies (GWAS) to the milder but more common adult-onset form of diabetes, type 2 diabetes. Conversely, loss-of-function mutations of K(ATP) are a major cause of familial hyperinsulinism, a hereditary disease found in children in which beta cells are persistently electrically active and secrete insulin in the face of normal or low glucose, causing life-threatening hypoglycemia. Another major cause of hyperinsulinism is excessive activity of the enzyme glucokinase, which also plays a key role in the DOM. The activity of the MO is controlled by the availability of the substrate of PFK, fructose-6-phosphate, which in turn depends on the external glucose concentration. This makes PFK a natural gateway for plasma glucose to control the oscillations of the beta cells and thence the pulses of insulin release. Calcium, and thereby insulin, oscillates when glucose is at an intermediate concentration, corresponding to typical post-prandial levels. In the earliest versions of the DOM, the MO drove the EO to produce the slow oscillations. However, recent evidence, described in the 2016 report, probing the oscillations of PKAR, a FRET-based sensor of fructose-1,6-bisphosphate (FBP), required a modification of the model to include a prominent but indirect role for calcium in regulating PFK. Calcium does this by activating pyruvate kinase, an enzyme downstream of PFK, which increases the rate of utilization of FBP, resulting in acceleration of the citric acid cycle and ATP production in the mitochondria. Thus, the activity of PFK is determined by the balance of input of substrate and consumption of product. In recognition of this integration of glycolytic and calcium-dependent elements of metabolism, we call the revised model the Integrated Oscillator Model (IOM). The IOM can account in detail for not only the existence of metabolic oscillations, but also the shape of oscillations in FBP and ATP, which is usually sawtoothed, rather than pulsatile, as predicted by the classic DOM. The IOM also offers a possible explanation for calcium oscillations sometimes seen when beta cells are exposed to amino acids rather than glucose. Amino acids enter metabolism in the mitochondria, bypassing glycolysis, so this phenomenon could not be accounted for the the classic DOM. In the IOM, in contrast, the action of calcium on the citric acid cycle, combined with its activation of ATP-consuming calcium pumps, is sufficient to account for slow calcium oscillations. A perspectives paper detailing this recent progress and experiments needed to further test the model is in review.